In our studies of the mechanism of hepatitis caused by inhalation anesthetics this year, it was found that the trifluoroacetyl chloride metabolite of the inhalation anesthetic halothane covalently altered a 170 kDa protein in the endoplasmic reticulum of rats. The protein was identified as UDP-glucose:glycoprotein glucosyltransferase, an enzyme that is involved in the formation of the correct conformation of glycoproteins. It was also discovered that the activity of the enzyme was inhibited by treatment of rats with halothane, suggesting that the covalent alteration of UDP-glucose:glycoprotein glucosyltransferase might be a factor contributing to the development of halothane hepatitis. In other studies, halothane hepatitis patients were found to have serum autoantibodies that reacted with a purified human liver protein of 58 kDa protein that was cloned from a human liver cDNA library and expressed in milligram quantities with the use of a baculovirus expression system. This finding supports the idea that halothane hepatitis has at least in part an immunopathological basis. Moreover, this year we reported the first case of hepatitis caused by the newest inhalation anesthetic desflurane and have provided evidence that the toxicity might have been caused by a cross-sensitization reaction, due to previous exposure and sensitization to halothane. We have continued to study the protein adducts of nonsteroidal anti- inflammatory agents, in an effort to determine how this widely used class of drugs causes hepatitis. This year the 110 kDa plasma membrane protein target of the nonsteroidal anti-inflammatory drug diclofenac has been identified from rats as dipeptidyl peptidase IV, which is identical to the lymphocyte accessory molecule, CD26. The enzyme was inactivated by diclofenac, suggesting a possible mechanism of hepatotoxicity. In addition, a 50 kDa endoplasmic reticulum protein target of diclofenac was identified as P450 2C11, an enzyme which has been associated with an immune-based hepatitis caused by another drug, tienilic acid. The other project that is currently being studied in my Section deals with the involvement of nitric oxide synthase and its product nitric oxide in various pathological conditions.